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Pentacycloundecane-diol-Based HIV-1 Protease Inhibitors: Biological Screening, 2D NMR, and Molecular Simulation Studies
Faculty
Not Specified
Year:
2012
Type of Publication:
Article
Pages:
1009-1019
Authors:
Soliman, Mahmoud E. S, Sayed, Yasien, Govender, Thavendran, Kruger, Hendrik G, Maguire, Glenn E. M, Pawar, Sachin A, Makatini, Maya M, Petzold, Katja, Arvidsson, Per I, Honarparvar, Bahareh
DOI:
10.1002/cmdc.201100512
Journal:
CHEMMEDCHEM WILEY-V C H VERLAG GMBH
Volume:
7
Research Area:
Pharmacology \& Pharmacy
ISSN
ISI:000304438900007
Keywords :
HIV-1 protease, inhibitors, molecular docking, peptides, transition-state analogues
Abstract:
Novel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild-type C-South African (C-SA) HIV-1 protease. Seven compounds are reported herein, three of which displayed IC50 values in the 0.50.6 mu M range. The cytotoxicity of PCU cage peptides toward human MT-4 cells appears to be several orders of magnitude less toxic than the current antiviral medications ritonavir and lopinavir. NMR studies based on the observed through-space 1H,1H distances/contacts in the EASY-ROESY spectra of three of the considered PCU peptide inhibitors enabled us to describe their secondary solution structure. Conserved hydrogen bonding interactions were observed between the hydroxy group of the PCU diol inhibitors and the catalytic triad (Asp25, Ile26, Gly27) of HIV protease in docking and molecular dynamics simulations. The biological significance and possible mode of inhibition by PCU-based HIV protease inhibitors discussed herein facilitates a deeper understanding of this family of inhibitors and their potential application to a vast number of alternative diseases related to proteases.
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